Since early May 2011, a large outbreak of enterohemorrhagic gastroenteritis and hemolytic uremic syndrome (HUS) related to infections with Shiga toxin-producing Escherichia coli O104:H4 (STEC O104:H4) had been reported in Germany, which marks one of the largest outbreaks ever described of the HUS worldwide. The HUS outbreak was unusual, and there were important differences between this outbreak and previous large outbreaks, primarily those of STEC O157:H7 both clinically and microbiologically. This outbreak highlights the importance of collaboration of all aspects of public health to detect the outbreak, to identify and characterize the causative agent, to find the vehicles of transmission, and to control the infection.